High-risk neuroblastoma (NB) is a deadly pediatric malignancy with less than 20% long term survival. Current therapeutic approaches rely on intensive chemotherapy, radiotherapy and radiotherapeutics. Despite its high relapse rate, high risk NB is a radiosensitive disease amenable to therapeutic radiopharmaceuticals. This has been shown clinically in multiple trials where the beta-emitting Iodine-131-metaiodobenzylguanidine ([131I]MIBG) showed the highest response rate of any tested single agent. However, the physical characteristics of beta particles makes them inefficient in the setting of micrometastatic disease. This is particularly relevant to high risk NB as it has been postulated that relapsed NB is caused primarily by residual micrometastatic disease in the bone marrow. The short path length and high relative biological effectiveness of alpha particles have the potential to overcome the limitations of beta particles and eradicate micrometastatic disease. Poly(ADP-ribose) Polymerase 1 has a variety of biological functions and is specifically located in the nucleus, directly on the chromatin. Furthermore, PARP-1 was shown to be overexpressed in high-risk NB and combined with its subcellular localization it is a unique therapeutic target for alpha-particle therapy. Through the functionalization of a small molecule PARP inhibitor with astatine-211 (At), we have developed a novel PARP-1 targeted alpha-emitting radiotherapeutic [(At]MM4). We hypothesize that delivering alpha-particles directly to the genome of NB cancer cells through targeting differential PARP-1 expression patterns in cancer vs. non-cancer tissue will be safe and effective at selectively destroying macro- and microtumors while sparing normal tissue. Through this proposal, we will fully characterize [At]MM4 for cellular lethality and potential mechanisms of resistance in high-risk NB using state-of-the-art CRISPR/Cas9 genome editing technology. In addition, using patient derived xenograft (PDX) models of NB we will perform the molecular characterization of NB PDX models and novel image guided therapy and survival studies.